Therapy of Type 2 Diabetes Mellitus: UPDATE Glycemic Goals in the Care of Patients with Type 2 Diabetes- 2013 ADA and AACE Guidelines: Room For Improvement (Be HAPPY/ Avoid Burnout, While Caring for Patients with DM) Stan Schwartz MD, FACP, FACE Affiliate, Main Line Health System Clinical Associate Professor of Medicine, Emeritus, U of Pa. Part 7 1

Renal Threshold SGLT-2 Inh. SGLT-2 Inhibitors DM NML 80 SGLT2-I

40-50% efficient as hepatic glucose production increased; Obviate with incretin Rx- yielding up to 1% drops Durable up to 1 year

Canagliflozin Efficacy

Side Effects SGLT-2 Inhibition cana cana cana Minimize by- push PO intake, fastidious bathroom habits; urinate after intercourse before sleep If baseline BP low- cut back or d/c diuretic or antihyperetensive Watch K+, if older, eGFR 45-60, on ACE / spironolactone

Other Meds with Glycemic Benefit Fast-acting Bromocryptine- drop 0.5-1% central dopaminergic effect on decreasing peripheral sympathetic tone decreasing insulin resistance Decreases CV outcomes 50% in 1 year Colsevelam- drop 0.5% lipid benefit (Ranolazine) drop 0.5-1.0% Decrease angina ( or equivalent) Decreases arrhythmia Improves diastolic dysfunction, thus-decreases edema of Pio-, Decreases HgA1c, FBS in glucose dependent fashion , no hypoglycemia

SCN Uses DOPAMINE The Biologic Clock Integrator of Signals ADAPTIVE IR Summer/ AM Winter/ overnight High Dopa Set Low IR Low Sym- pathetic tone Low Dopa Set High IR High Sympathetic tone Persistent Maladaptive IR Hyperglycemia, high fat/sugar diets, altered sleep/wake cycles, no exercise, stress patients with genetically susceptible b-cell Diabetes Mellitus

Bromocriptine QR: Proposed mechanism of action Morning administration (within 2 hours of waking) of AGENT Corrects Low dopaminergic tone in hypothalamus in early morning in diabetes Restoration of morning peak in dopaminergic activity (via D2 receptor-mediated activity) Sympathetic tone HPA axis tone  Hepatic gluconeogenesis  FFA and TG  Insulin resistance  Inflammation/hypercoagulation Sympathetic tone HPA axis tone  Hepatic gluconeogenesis  FFA and TG  Insulin resistance  Inflammation/hypercoagulation The central and peripheral dopaminergic system is involved in the regulation of energy homeostasis Dopaminergic neurotransmission is thought to affect both glucose and lipid metabolism, and in patients with diabetes there is an early morning dip in hypothalamic dopaminergic tone which leads to an increase in sympathetic tone, activation of the hypothalamic-pituitary-adrenal axis, and potentiates systemic low-grade inflammation. These actions precipitate abnormalities in glucose metabolism, insulin resistance and cardiovascular pathology. When administered within 2 hours of waking, CYCLOSET is thought to restore the dopaminergic activity via its D2-mediated action, improving postprandial glucose (at each of the three standard meals of the day) without increasing insulin secretion. It also reduces triglycerides and free fatty acids. Decreased postprandial glucose levels Reduction in insulin resistance Day-long reduction in plasma glucose, TGs and FFAs Impaired glucose metabolism, hyperglycemia and insulin resistance Adverse cardiovascular pathology Fonseca. Use of Dopamine agonists in Type-2-Diabetes. Oxford American Pocket Cards. OUP, 2010 Cincotta. Hypothalamic role in Insulin Resistance and insulin Resistance Syndrome. Frontiers in Animal Diabetes Research Series. Taylor and Francis, Eds Hansen, B Shafrir, E London, pp 271-312, 2002 2-CYC10529 8

Therapy for Type II Diabetes 9

Targets for Glycemic Control A1C (%) Normal: 4-6% Fasting/Preprandial (mg/dL) (plasma equivalent) Postprandial (mg/dL) (2-hour) ACE <6.5 <110 <140 ADA <7.0 90-130 <180* * Peak MANDATORY Presenter reviews targets for glycemic control as established by the American Diabetes Association and the American College of Endocrinology. Goals for individual patients may vary. Aim for the Lowest A1C Possible without Hypoglycemia. American Diabetes Association. Clinical Practice Recommendations. Diabetes Care. 2004,27:S15-S35 The American Association of Clinical Endocrinologists. Medical Guidelines for the Management of Diabetes Mellitus. Endocr Pract. 2002; 8(Suppl. 1): 40-82 10

Inc PPG increases Micro- and macro- vascular disease Thus , to get to glycemic goals, one must control PPG as well as FBS. (incretins, alpha-glucosidase inhibitors, TZDs)

Reduce Variability and Prevent Build-up of Metabolic Memory Augers for Avoiding Step-Care Therapy; use Early CombinationTherapy